Early substance use (E-SU) is known to increase the risk of abuse, dependence, addiction, polydrug use, and other problematic outcomes in adulthood. Therefore, the U.S. Surgeon General's office has issued a call-to-action to stop underage use, especially in adolescents less than 15 years of age. This goal is especially compelling for American Indians, for some of whom lifetime burden from substance use is particularly high. In order to prevent E-SU effectively, however, we need firm evidence regarding the childhood environment that increases (or decreases) children's risk for E-SU. Yet very little is presently known about early environmental risks for E-SU specifically and in diverse samples, which constitutes a major gap in knowledge with substantial implications for prevention. The proposed research fills in this gap by applying a developmental life course model to longitudinal data spanning childhood to age 30. Specifically, we propose to examine developmental features of environmental risk, including distinctions of timing, duration, and co-occurrence with other risks; the earliest ages of onset; protective factors that could neutralize risk; and vulnerability factors that could exacerbate the contributions of the risk environment to E-SU. Many studies are also not informative about sex differences in associations between risk and E-SU or co-occurring adolescent psychological, social, and biological transitions such as puberty. The proposed program of secondary data analyses tests a life-course developmental model of E-SU that examines whether youth with E-SU are characterized by distinct profiles of risk and protective factors compared to their peers. Because E-SU occurs during periods of major psychosocial and brain developments, our life-course model also tests whether E-SU itself contributes to poor adult outcomes, even when holding constant prior environmental risk and child behaviors. Data come from a large ongoing, community-representative, prospectively longitudinal, study, the Great Smoky Mountains Study (GSMS). The GSMS has assessed a wide array of risk factors, use of many different substances, additional psychiatric symptoms and disorders, and the developmental transitions from childhood to young adulthood on up to eleven occasions spanning ages 9 to 30, providing an unparalleled opportunity to study pathways to and from E-SU. The dataset also includes a sizable American Indian subsample, allowing us to test our life-course model of E-SU in this understudied population. The proposed analyses offer an unprecedented opportunity to generate new insights into risk, resilience, and outcomes for E-SU in rural American Indian and Anglo females and males. Results from the proposed research will have implications for both prevention and intervention research by identifying who is most at risk for early substance use, when, and why. Results will also have implications for basic research investigating associations between E-SU and long- term outcomes, because such associations can only be understood when the early risk environment of E-SU is well-characterized and taken into account.